Project Summary The Diabetes Control and Complications Trial (DCCT, 1983-1993) compared intensive therapy aimed at near normal glycemia versus conventional therapy with no specific glucose targets in 1441 subjects with type 1 diabetes (T1DM) over a mean follow-up of 6.5 yrs. Intensive therapy reduced the risks of retinopathy, nephropathy, and neuropathy by 35-76%, hyperglycemia being a primary determinant of complications. We also described potential adverse effects of intensive therapy; assessed its effects on cardiovascular disease (CVD) risk factors, neurocognition and quality of life; and projected the lifetime health-economic impact. DCCT intensive therapy was then adopted world-wide as standard-of-care for T1DM. The Epidemiology of Diabetes Interventions and its Complications (EDIC, 1994-present) is the observational follow-up study of the DCCT cohort, with 94% of those surviving actively participating. Participants are evaluated annually. CVD events and deaths are carefully documented and adjudicated. EDIC has notably shown that the early beneficial effects of intensive versus conventional therapy on complications have persisted for more than 15 years despite the similar HbA1c levels in the two groups during EDIC, termed metabolic memory. Former intensive therapy also greatly reduced the risk of CVD events, advanced microvascular complications, such as chronic kidney disease and eye complications requiring surgery, and mortality. DCCT/EDIC collaborators have also conducted numerous ancillary studies with separate funding. The overarching goals for the next 5 years (2017-22) will be to take advantage of the loyal and highly characterized DCCT/EDIC cohort and study the occurrence of physical and cognitive dysfunction and more advanced complications, and their risk factors, in this aging type 1 diabetes population. Since current-day diabetes therapy has increased the longevity of people with type 1 diabetes, it is critical to understand how aging affects patients with type 1 diabetes and to define the risk factors for the occurrence of aging sensitive deficits. In addition, the accrual of long-term severe complications will allow the study of their risk factors and the quality-of-life and health economic consequences. The specific scientific aims are to 1) examine the prevalence of cognitive, affective, and physical impairments in T1DM, and the association of DCCT treatment arm, glycemia, and established and putative non-glycemic risk factors on important domains of aging: cognitive, affective and physical impairments, functional limitations, disability, quality-of-life, frailty, falls, fractures, and survival; 2) analyze the risk factors/mechanisms associated with severe/advanced microvascular complications; 3) analyze the risk factors/mechanisms associated with CVD and mortality; 4) develop new research approaches to measure the progression of diabetes outcomes (vectors) in T1DM, derived from the unique long-term, longitudinal follow-up of the DCCT cohort; and 5) study the long-term economic consequences of T1DM.